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Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity


Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABAA receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6100R/100R and Gabra6100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.

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Figure 1: The α6-R100Q polymorphism leads to a marked increase in ethanol sensitivity when expressed with β3 and δ subunits.
Figure 2: A single-nucleotide polymorphism (a guanine-to-adenine substitution) in the gene encoding the rat GABAA receptor α6 subunit (Gabra6) is common in Sprague-Dawley rats obtained from Charles River Laboratories.
Figure 3: Ethanol enhances granule cell tonic GABA current, and the enhancement is larger in Gabra6100Q/100Q rats.
Figure 4: Tonic GABA current in granule cells is enhanced by low concentrations of ethanol in Gabra6100R/100R and Gabra6100Q/100Q rats.
Figure 5: Rats homozygous for the α6-100Q polymorphism show increased alcohol-induced motor impairment as compared with Gabra6100R/100R rats.


  1. 1

    Vallee, B.L. Alcohol in the western world. Sci. Am. 278, 80–85 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Davies, A.G. et al. A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115, 655–666 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Kobayashi, T. et al. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat. Neurosci. 2, 1091–1097 (1999).

    CAS  Article  Google Scholar 

  4. 4

    Lewohl, J.M. et al. G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action. Nat. Neurosci. 2, 1084–1090 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Hodge, C.W. et al. Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKCε. Nat. Neurosci. 2, 997–1002 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Lovinger, D.M., White, G. & Weight, F.F. Ethanol inhibits NMDA-activated ion current in hippocampal neurons. Science 243, 1721–1724 (1989).

    CAS  Article  Google Scholar 

  7. 7

    Mihic, S.J. et al. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 389, 385–389 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Suzdak, P.D. et al. A selective imidazobenzodiazepine antagonist of ethanol in the rat. Science 234, 1243–1247 (1986).

    CAS  Article  Google Scholar 

  9. 9

    Sundstrom-Poromaa, I. et al. Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat. Neurosci. 5, 721–722 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Wallner, M., Hanchar, H.J. & Olsen, R.W. Ethanol enhances α4β3δ and α6β3δ GABAA receptors at low concentrations known to affect humans. Proc. Natl. Acad. Sci. USA 100, 15218–15223 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Choi, D.S. et al. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat. Neurosci. 7, 855–861 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Macdonald, R.L. & Olsen, R.W. GABAA receptor channels. Annu. Rev. Neurosci. 17, 569–602 (1994).

    CAS  Article  Google Scholar 

  13. 13

    Mohler, H., Crestani, F. & Rudolph, U. GABAA-receptor subtypes: a new pharmacology. Curr. Opin. Pharmacol. 1, 22–25 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W. & Sperk, G. GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815–850 (2000).

    CAS  Article  Google Scholar 

  15. 15

    Peng, Z. et al. GABAA receptor changes in δ subunit-deficient mice: altered expression of α4 and γ2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Nusser, Z., Sieghart, W. & Somogyi, P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18, 1693–1703 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Campos, M.L., de Cabo, C., Wisden, W., Juiz, J.M. & Merlo, D. Expression of GABAA receptor subunits in rat brainstem auditory pathways: cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus. Neuroscience 102, 625–638 (2001).

    CAS  Article  Google Scholar 

  18. 18

    Saxena, N.C. & Macdonald, R.L. Properties of putative cerebellar GABAA receptor isoforms. Mol. Pharmacol. 49, 567–579 (1996).

    CAS  PubMed  Google Scholar 

  19. 19

    Nusser, Z. et al. Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene. Eur. J. Neurosci. 11, 1685–1697 (1999).

    CAS  Article  Google Scholar 

  20. 20

    Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W. & Farrant, M. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409, 88–92 (2001).

    CAS  Article  Google Scholar 

  21. 21

    Stell, B.M., Brickley, S.G., Tang, C.Y., Farrant, M. & Mody, I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors. Proc. Natl. Acad. Sci. USA 100, 14439–14444 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Rossi, D.J. & Hamann, M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity α6 subunit GABAA receptors and glomerular geometry. Neuron 20, 783–795 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Chadderton, P., Margrie, T.W. & Hausser, M. Integration of quanta in cerebellar granule cells during sensory processing. Nature 428, 856–860 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Korpi, E.R., Kleingoor, C., Kettenmann, H. & Seeburg, P.H. Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor. Nature 361, 356–359 (1993).

    CAS  Article  Google Scholar 

  25. 25

    Saba, L. et al. The R100Q mutation of the GABAA α6 receptor subunit may contribute to voluntary aversion to ethanol in the sNP rat line. Brain Res. Mol. Brain Res. 87, 263–270 (2001).

    CAS  Article  Google Scholar 

  26. 26

    Farrant, M. & Cull-Candy, S. GABA receptors, granule cells and genes. Nature 361, 302–303 (1993).

    CAS  Article  Google Scholar 

  27. 27

    Radcliffe, R.A. et al. Behavioral characterization of alcohol-tolerant and alcohol-nontolerant rat lines and an f(2) generation. Behav. Genet. 34, 453–463 (2004).

    Article  Google Scholar 

  28. 28

    Wisden, W., Korpi, E.R. & Bahn, S. The cerebellum: a model system for studying GABAA receptor diversity. Neuropharmacology 35, 1139–1160 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Poltl, A., Hauer, B., Fuchs, K., Tretter, V. & Sieghart, W. Subunit composition and quantitative importance of GABAA receptor subtypes in the cerebellum of mouse and rat. J. Neurochem. 87, 1444–1455 (2003).

    Article  Google Scholar 

  30. 30

    Carta, M., Mameli, M. & Valenzuela, C.F. Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability. J. Neurosci. 24, 3746–3751 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Kaneda, M., Farrant, M. & Cull-Candy, S.G. Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum. J. Physiol. (Lond.) 485, 419–435 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Overstreet, L.S. & Westbrook, G.L. Paradoxical reduction of synaptic inhibition by vigabatrin. J. Neurophysiol. 86, 596–603 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Nusser, Z. & Mody, I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J. Neurophysiol. 87, 2624–2628 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Semyanov, A., Walker, M.C., Kullmann, D.M. & Silver, R.A. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Semyanov, A., Walker, M.C. & Kullmann, D.M. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6, 484–490 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Jones, A. et al. Ligand-gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression. J. Neurosci. 17, 1350–1362 (1997).

    CAS  Article  Google Scholar 

  37. 37

    Mitchell, S.J. & Silver, R.A. Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38, 433–445 (2003).

    CAS  Article  Google Scholar 

  38. 38

    Korpi, E.R. et al. Cerebellar GABAA receptors in two rat lines selected for high and low sensitivity to moderate alcohol doses: pharmacological and genetic studies. Alcohol 9, 225–231 (1992).

    CAS  Article  Google Scholar 

  39. 39

    Vekovischeva, O.Y., Haapalinna, A., Sarviharju, M., Honkanen, A. & Korpi, E.R. Cerebellar GABAA receptors and anxiolytic action of diazepam. Brain Res. Mol. Brain Res. 837, 184–187 (1999).

    CAS  Google Scholar 

  40. 40

    Korpi, E.R. et al. Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from α6-subunit-deficient mice. Eur. J. Neurosci. 11, 233–240 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Homanics, G.E. et al. Mice devoid of GABAA receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl. Acad. Sci. USA 94, 4143–4148 (1997).

    CAS  Article  Google Scholar 

  42. 42

    Homanics, G.E. et al. Gene knockout of the α6 subunit of the GABAA receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol. 51, 588–596 (1997).

    CAS  Article  Google Scholar 

  43. 43

    Uusi-Oukari, M. et al. Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABAA receptor β2-α6-α1-γ2 subunit gene cluster. Mol. Cell. Neurosci. 16, 34–41 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Rudolph, U. et al. Benzodiazepine actions mediated by specific GABAA receptor subtypes. Nature 401, 796–800 (1999).

    CAS  Article  Google Scholar 

  45. 45

    McKernan, R.M. et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat. Neurosci. 3, 587–592 (2000).

    CAS  Article  Google Scholar 

  46. 46

    Low, K. et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134 (2000).

    CAS  Article  Google Scholar 

  47. 47

    Jurd, R. et al. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABAA receptor β3 subunit. FASEB J. 17, 250–252 (2003).

    CAS  Article  Google Scholar 

  48. 48

    Wei, W., Faria, L.C. & Mody, I. Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J. Neurosci. 24, 8379–8382 (2004).

    CAS  Article  Google Scholar 

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We thank C. Gundersen and the UCLA Anesthesiology Department for providing X. laevis oocytes, A. Taylor and D. Tio for help with blood alcohol analysis, and K. Olofsdotter-Otis for helpful comments on the manuscript. The work was supported by a Human Frontiers Science Program Long Term Fellowship to P.D.D. and by US National Institutes of Health grants AA015460 to H.J.H, NS41651 to T.S.O., and NS35985 and AA07680 to R.W.O.

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Correspondence to Thomas S Otis or Martin Wallner.

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Hanchar, H., Dodson, P., Olsen, R. et al. Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity. Nat Neurosci 8, 339–345 (2005).

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